Aging is a complex biological process that is modulated by numerous genetic and environmental factors. Among the environmental factors, dietary nutrients are critical in modulating healthspan and lifespan. Nutrient imbalance has been shown to post great risks to human health, especially to the elderly population. Dietary macronutrients, such as sugar, protein and fat, can interact with each other and have significant impact on health. Therefore, it is critical to take into account diet composition in elucidating molecular mechanisms of aging and in developing effective interventions for promoting healthy aging. Mitochondrial genes have been shown to play a key role in modulating lifespan and are implicated in numerous age-related diseases, such as Parkinsons and Alzheimers diseases. However, how mitochondrial genes interact with dietary macronutrients to modulate lifespan and healthspan remains incompletely elucidated. To this end, we have focused on studying the function of ATP synthase subunit d (ATPsyn-d) in modulating lifespan under various dietary conditions in Drosophila. We have found that ATPsyn-d interacts with dietary macronutrients to modulate lifespan likely through altering the accumulation of oxidative damage and protein aggregates, the resistance to oxidative stress and the expression of numerous genes involved in metabolism, proteolysis and innate immune response. We have also demonstrated that ATPsyn-d interacts with MAP kinase (MAPK) and TOR signaling pathways to modulate lifespan. This line of research has been accepted for publication in Cell Reports (2014 in press). Our study reveals the unexpected interaction between mitochondrial genes and nutritional factors at least partially through TOR signaling in modulating lifespan. Our findings on the interaction between ATPsyn-d and TOR signaling in aging prompted us to propose that the hypothesis that genetic background is critical for the effect of nutraceuticals and pharmaceuticals in promoting longevity. To test this hypothesis, we have determined the effect of rapamycin on lifespan in wild type and ATPsyn-d knockdown flies. Rapamycin is known to suppress rapamycin and promotes longevity in various species including flies and rodents. We have found that, while rapamycin feeding can extend lifespan of wild type flies, it significantly reduces lifespan of flies with reduced expression of ATPsyn-d. This line of research has been presented in our aforementioned paper accepted for publication in Cell Reports 2014. These findings stress the importance to take into account the genetic background in implementing interventions for promoting longevity and healthspan and provide a framework for designing effect aging interventions. In addition, in collaboration with Drs. Ming Zhan and Bing Yu, we have investigated the regulatory network among microRNA, NF-kappaB and p53 in head and neck squamous cell carcinoma. This line of work has been published in PLoS ONE 2013. This work will be valuable for studying aging-related diseases, including cancer. In summary, we have made significant progress towards understanding molecular mechanisms underlying aging and age-related diseases. We have demonstrated an unexpected function of ATP synthase in modulating lifespan besides its well-known function in generating ATP. We have investigated the gene-environment interactions in aging, which is a key to tackle aging and age-related diseases. These studies are valuable for advancing the objectives of the Translational Gerontology Branch and the mission of the NIA to understand the basic biology of aging and develop efficient interventions for humans.